Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control

Abstract

The microbiome affects eukaryotic host cells via many metabolites, including the well-studied queuine as substrate for host tRNA queuosine modification. The microbial metabolite pre-queuosine 1 (preQ₁) is produced in the bacterial tRNA queuosine biosynthesis pathway, with unknown effects on host cell biology. Here we show that preQ₁ strongly represses cell proliferation in both human and mouse cells. Queuine reverses this effect by competing with preQ₁ to modify the same tRNA. PreQ₁ is detectable in the plasma and tissues of mice, and its injection suppresses tumour growth in a mouse cancer model. Mechanistically, preQ₁ reduces cognate tRNA levels specifically, as well as codon-dependent translation of housekeeping genes. We identify the endoplasmic reticulum-localized inositol-requiring enzyme 1 (IRE1) ribonuclease as the enzyme responsible for the selective degradation of preQ₁-modified tRNAs on translating ribosomes. Our results identify two microbial metabolites competing for host tRNA modification, which elicits translation quality control and impacts cell proliferation.